Although AKT1 (v-akt murine thymoma viral oncogene homologue 1) kinase is a central member of possibly the most frequently activated proliferation and survival pathway in cancer, mutation of AKT1 has not been widely reported. Here we report the identification of a somatic mutation in human breast, colorectal and ovarian cancers that results in a glutamic acid to lysine substitution at amino acid 17 (E17K) in the lipid-binding pocket of AKT1. Lys 17 alters the electrostatic interactions of the pocket and forms new hydrogen bonds with a phosphoinositide ligand. This mutation activates AKT1 by means of pathological localization to the plasma membrane, stimulates downstream signalling, transforms cells and induces leukaemia in mice. This mechanism indicates a direct role of AKT1 in human cancer, and adds to the known genetic alterations that promote oncogenesis through the phosphatidylinositol-3-OH kinase/AKT pathway. Furthermore, the E17K substitution decreases the sensitivity to an allosteric kinase inhibitor, so this mutation may have important clinical utility for AKT drug development.

LY121019 (N-p-octyloxybenzoylechinocandinB nucleus) is a semisynthetic antifungal antibiotic that possesses potent anti-Candida activity. The MICS0 and the MIC90 for both LY121019 and amphotericin B were 0.625 and 1.25 t g/ml, respectively.Only an 8-fold increase in the MIC against C. albicans occurred during 34-day exposure to subinhibitory concentrations indicating that LY121019 has a low potential for causing resistance development. Scanning electron microscopic studies revealed that LY121019 caused severe damage to the C. albicans cell. The ED50's for LY121019 and amphotericin B administered parenterally to mice were 7.4 and 2.5 mg/kg, respectively. Parenterally administered LY121019 at doses of 6.25 mg/kg significantly reduced the recovery of C. albicans from infected mouse kidneys. Orally administered 50 and 100 mg/kg doses of LY121019 were effective in eliminating C. albicans from the gastrointestinal tract of infected mice. Topical application of 5 % LY12I019 was as effective as 3 % nystatin in the treatment of superficial C. albicans infections. Local administration of LY121019, nystatin, or miconazole was effective against rat vaginal candidiasis. LY121019 was administered intravenously to dogs at doses up to 100 mg/kg/day, 5 days a week for 3 months; all dogs survived. Compound related effects included a histaminelike reaction, increased serum alkaline phosphatase and SGPT, fatty vacuolization of the liver, and some tissue damage at the injection site. The no effect dose in dog was 10 mg/kg. LY121019 had no more than 1/20 the toxicity of amphotericin B in the dog. EchinocandinB and aculeacin are related polypeptide antifungal antibiotics with a narrow spectrum of antifungal activity although highly active against yeasts1.2)• We are reporting on the antiCandida activity and toxicology of LY121019, a novel analog of the polypeptide antifungal antibiotic echinocandin B (Fig. 1). The study involves comparison of the in vitro and in vivo anti-Candida activity and toxicology of LY121019 with these qualities of clinically used parenteral and topical antifungal agents.

DNA-dependent RNA polymerase II (RNAP II) largest subunit RPB1 C-terminal domain (CTD) kinases, including CDK9, are serine/threonine kinases known to regulate transcriptional initiation and elongation by phosphorylating Ser 2, 5, and 7 residues on CTD. Given the reported dysregulation of these kinases in some cancers, we asked whether inhibiting CDK9 may induce stress response and preferentially kill tumor cells. Herein, we describe a potent CDK9 inhibitor, LY2857785, that significantly reduces RNAP II CTD phosphorylation and dramatically decreases MCL1 protein levels to result in apoptosis in a variety of leukemia and solid tumor cell lines. This molecule inhibits the growth of a broad panel of cancer cell lines, and is particularly efficacious in leukemia cells, including orthotopic leukemia preclinical models as well as in ex vivo acute myeloid leukemia and chronic lymphocytic leukemia patient tumor samples. Thus, inhibition of CDK9 may represent an interesting approach as a cancer therapeutic target, especially in hematologic malignancies.

The PI3K/AKT/mTOR pathway is among the most frequently altered pathways in cancer cell growth and survival.